Summary
Three compounds in this knowledge base are acylated synthetic peptides acting at incretin receptors, and the class distinction between them is simply how many receptors each engages. Semaglutide is a 31-residue analogue of human glucagon-like peptide-1 (GLP-1) which selectively binds to and activates the GLP-1 receptor 12. Tirzepatide is a 39-residue peptide acting as an agonist at both the glucose-dependent insulinotropic polypeptide (GIP) receptor and the GLP-1 receptor 34. Retatrutide, development code LY3437943, is a 39-residue peptide described in WHO proposed international non-proprietary name list 128 as an agonist of the glucagon, GIP and GLP-1 receptors 5.
The three also sit at different points of the documentary record. Semaglutide and tirzepatide are active substances of medicines authorised in the United States, the European Union and the United Kingdom 67891011. Retatrutide holds no marketing authorisation in any jurisdiction examined 121314.
Three receptor profiles
The receptor assignments are stated by regulators and by nomenclature authorities rather than inferred. The EU summary of product characteristics for semaglutide records 94% sequence homology to human GLP-1 and selective binding to and activation of the GLP-1 receptor 1. For tirzepatide the same document class describes a long-acting agonist highly selective for the human GIP and GLP-1 receptors, with activity at the GIP receptor similar to that of native GIP and activity at the GLP-1 receptor lower than that of native GLP-1; it adds that both receptors are expressed in brain areas involved in appetite regulation and that GIP receptors are present on adipocytes 9. For retatrutide there is no regulatory product information, because no product is authorised; the receptor profile rests on the WHO entry and on the FDA Global Substance Registration System, which records three target relationships of agonist type, to the GLP-1 receptor, the gastric inhibitory polypeptide receptor and the glucagon receptor 515.
Two consequences follow for reading the literature. The addition of a receptor is a change in the set of targets engaged, not a graded version of the same pharmacology, and the published phase 2 papers for retatrutide describe the three-receptor pharmacology rather than a more potent GLP-1 effect 1617. And the peptide backbones differ in origin: unlike an acylated GLP-1 analogue, the peptide component of tirzepatide is based on the GIP sequence 34.
Shared design features
Despite the different receptor sets, the three molecules are built to a recognisably common plan.
Aib substitution. Semaglutide is described in the EMA assessment report as an Aib8, Arg34-GLP-1(7-37) analogue; the US labels state that the substitution at position 8 stabilises the molecule against dipeptidyl peptidase-4, and that the substitution at position 34 ensures that only one fatty di-acid is attached 1819. Tirzepatide carries two non-coded 2-aminoisobutyric acid residues, at positions 2 and 13 320. Retatrutide carries 2-methylalanine, that is Aib, at positions 2 and 20, together with 2-methyl-L-leucine at position 13 521.
Acylation with a fatty di-acid and a linker. In semaglutide the epsilon-amino group of Lys26 bears a side chain built from two 8-amino-3,6-dioxaoctanoic acid spacers, one gamma-glutamic acid spacer and 1,18-octadecanedioic acid 18. In tirzepatide the lysine at position 20 is attached to 1,20-eicosanedioic acid, a C20 fatty di-acid, through a linker of one gamma-glutamic acid and two 8-amino-3,6-dioxaoctanoic acid units 320. In retatrutide the epsilon-amino group of Lys17 is acylated with one 2-[2-(2-aminoethoxy)ethoxy]acetyl unit, an L-gamma-glutamyl spacer and a 19-carboxynonadecanoyl C20 alpha,omega-fatty diacid bearing a free terminal carboxylate 52122.
Albumin binding. The stated purpose of the acyl chain is the same in each case. The US label for semaglutide attributes albumin binding to acylation at position 26 with a hydrophilic spacer and a C18 fatty di-acid, and the EU summary of product characteristics attributes the approximately one-week half-life to that binding, with more than 99% of circulating peptide bound, which reduces renal clearance and protects the molecule from metabolic degradation 191. For tirzepatide the US label states that the C20 fatty di-acid enables albumin binding and prolongs the half-life, and reports 99% binding to plasma albumin with a half-life of approximately 5 days 423. For retatrutide no albumin-binding figure or half-life appears in any allow-listed source retrieved for the dossier 155.
C-terminal amidation. Tirzepatide terminates in L-serinamide at position 39, and retatrutide likewise carries L-serinamide at position 39 35.
A practical corollary applies to all three. A plain one-letter sequence string conceals every one of these features: the GSRS string for semaglutide writes position 2 as alanine while recording the Aib substitution separately, the GSRS subunit string for tirzepatide writes both Aib positions as ordinary coded residues, and both GSRS records for retatrutide carry an estimated formula for the bare 39-residue sequence with an empty modifications section 24201522.
How the published evidence differs in size and stage
The three compounds are at three stages of the trial record, and the difference is one of quantity and publication status rather than of kind.
For semaglutide the dossier records eight phase 3 trials with published primary papers, spanning glycaemic, cardiovascular, kidney, body-weight and liver endpoints, among them an event-driven cardiovascular trial with 17,604 participants, a kidney outcomes trial with 3,533 stopped early for efficacy at a prespecified interim analysis, and a cardiovascular trial with 9,650 252627. The dossier notes that most of the SUSTAIN, PIONEER and STEP programme publications were not retrieved, so its table is a documented selection rather than the complete literature 28.
For tirzepatide the dossier records seven phase 3 trials with published primary papers, including a cardiovascular outcomes trial with 13,299 randomised participants and trials with sleep-apnoea and heart-failure endpoints 293031. Two of the seven used a GLP-1 receptor agonist as the active comparator rather than placebo, which is the only place in this literature where two of the compounds discussed here were administered within one randomised design; the numerical outcomes of those trials are reported in the tirzepatide monograph and are not reproduced here 3233.
For retatrutide the published record is shorter and partly unpublished. Two phase 2 trials are peer-reviewed with posted registry results, one in 338 participants and one in 281, and one phase 3 trial in 537 participants has been published 161734. Four further phase 3 readouts, TRIUMPH-1 to TRIUMPH-4, exist only as company press releases and conference presentations, with no peer-reviewed publication and no posted registry results as of 22 September 2026 35363738. The developer states that retatrutide has not been approved by any regulatory agency and that it planned a US submission in the first quarter of 2027 3936.
Semaglutide and tirzepatide: licensed medicines with completed phase 3 programmes and published primary papers 4032. Retatrutide: investigational, with two published phase 2 trials, one published phase 3 trial and four phase 3 readouts reported only by announcement 163436.
Manufacture, characterisation and anti-doping status
The manufacturing routes diverge along the same line as the evidence. The peptide backbone of licensed semaglutide is produced by recombinant DNA technology in Saccharomyces cerevisiae and is then chemically modified and purified 18. The licensed tirzepatide active substance is made by solid-phase peptide synthesis followed by chromatographic purification, and process chemists at the originator have described diketopiperazine formation and associated double-deletion impurities arising at the C-terminal proline-proline-serine region 341. Synthesis of retatrutide is reported to rely predominantly on solid-phase peptide synthesis, with a hydrophobic-tag-assisted liquid-phase route also described 42. No pharmacopoeial monograph was retrieved for any of the three 18312. A validated multiplexed liquid chromatography high-resolution mass spectrometry method covering nine peptide GLP-1 receptor agonists, retatrutide among them, has been published 43.
In anti-doping, neither semaglutide nor tirzepatide is named on the 2026 Prohibited List, and both appear on the 2026 Monitoring Program, which that document defines as covering substances which are not on the Prohibited List 4445. Retatrutide is likewise unnamed on the list, but as a substance without current approval by any governmental regulatory health authority it falls within class S0, non-approved substances, which is prohibited at all times 4647.
What this comparison does not establish
Receptor count, acyl-chain length and trial-programme size are properties of molecules and of literatures. None of them is a statement about suitability for any purpose, and nothing in the published record retrieved for these dossiers compares the three compounds as a complete set in a single randomised design 323334. Three specific gaps are recorded. The molecular weight of retatrutide rests on a single database record, so the dossier's two-source requirement is unmet for that field 485. No solubility, storage or solution-stability figure for retatrutide appears in any allow-listed source 1536. And the GSRS formula for each of the three disagrees with the corresponding regulatory or nomenclature value, in every case flagged within the registry itself as estimated 242015.